Coronary heart disease is the leading cause of death in the U.S., and patients who survive a coronary artery occlusion have a high risk for cardiac arrhythmias and sudden cardiac death. Spatial heterogeneity of sympathetic transmission is a major contributor to post-infarct arrhythmias and sudden cardiac death after myocardial infarction (MI), and sympathetic denervation predicted arrhythmia risk in recent human studies. We have identified two distinct types of sympathetic denervation after MI: 1) persistent denervation of the infarct/scar and adjacent border zone myocytes, and 2) transient denervation of uninjured peri-infarct myocardium. This proposal will develop methods to prevent or reverse both types of denervation, and determine if restoring sympathetic innervation throughout the ventricle decreases arrhythmia susceptibility. The infarct remains denervated after MI due to chondroitin sulfate proteoglycans (CSPGs). We identified protein tyrosine phosphatase receptor sigma (PTP?) as the major CSPG receptor in sympathetic neurons, and found that removing PTP? resulted in reinnervation of the border zone and hyperinnervation of the cardiac scar. Preliminary data suggest that eliminating PTP? normalizes cardiac electrophysiology and renders hearts surprisingly resistant to post-MI arrhythmias. This suggests that restoring sympathetic innervation has a beneficial effect on arrhythmia susceptibility. However, it's not clear if re-innervation is the key to preventing arrhythmias, or if other actions of PTP? contribute to decreased arrhythmia susceptibility in PTP? +/-hearts. We hypothesize that the major action of PTP? is to prevent reinnervation via interactions with CSPGs (Aim 1), and that restoring sympathetic innervation will decrease arrhythmia susceptibility (Aim 2). Peri-infarct myocardium is transiently denervated 1 and 3 days after MI and loss of sympathetic fibers outside the infarct requires activation of the p75 neurotrophin receptor. We identified ProNGF and a form of Brain Derived Neurotrophic Factor (either proBDNF or BDNF) as p75 ligands that are elevated in the heart after MI. We will test the hypothesis that pro-neurotrophins and/or BDNF stimulate peri-infarct denervation, and that preventing peri- infarct denervation will decrease arrhythmia susceptibility (Aim 3). We have assembled an outstanding team of experts along with unique animal models and novel genetic tools to assist us in completing these studies. This work will test directly if manipulating cardiac nerves after MI can normalize cardiac electrophysiology and decrease arrhythmia frequency, opening a new avenue for therapeutic development.